Delivery system for radiation therapy

ABSTRACT

A device is used to precisely deliver the treatment plan created by an automatic planning system by positioning a single low energy radiation source, or a plurality of low energy sources connected to each other, in a predetermined parallel, planar, or similar geometry, each source equipped with blocking and attenuation mechanisms, thereby delivering a plurality of parallel overlapping beams indexed on a millimeter or submillimeter grid such that a concentration of dose is achieved at a variable depth in tissue relative to the dose where the radiation first enters the tissue. A plurality of overlapping beams indexed on a millimeter or submillimeter grid can converge on a target volume loaded with gold nanoparticles to deliver a tumorcidal dose of radiation in as little as a single session to tumor cells but not to normal cells or to deliver serial radiosurgical treatments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application claiming priority from U.S.patent application Ser. No. 12/251,298, now U.S. Pat. No. 8,050,384,entitled “DELIVERY SYSTEM FOR RADIATION THERAPY,” with filing date Oct.14, 2008, which is a continuation of U.S. patent application Ser. No.11/149,565, now abandoned entitled “Kilovoltage delivery system forradiation therapy,” with filing date Jun. 9, 2005, both of which areincorporated herein by reference. U.S. patent application Ser. No.11/149,565 claims priority to U.S. provisional patent application, Ser.No. 60/578,720, with filing date Jun. 10, 2004 and U.S. provisionalpatent application, Ser. No. 60/578,721, with filing date Jun. 10, 2004.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

None

BACKGROUND

1. Field of the Invention

This invention relates to the use of low energy radiation as a treatmentfor cancer and other conditions.

2. Description of Prior Art

Radiation Therapy for Targets in Proximity to Treatment Device

Radiation therapy has been a very successful and well-utilized means forcontrolling and sometimes even curing cancer. Most commonly delivered inan outpatient setting over several weeks, RT is delivered usually usingmachines capable of delivering high energy photons (megavoltage, MV) ina very controlled manner using ancillary devices such as multileafcollimators, intensity modulating delivery paradigms, and portal imagingsystems for monitoring treatment delivery. Since the high energy of thex-rays generated by these machines can penetrate very deeply, thesemachines can be used to treat tumors occurring deep inside the body.

Superficial Cancers

Unfortunately, sophisticated MV delivery systems may not be able totreat superficial cancers such as those of the skin or nonmalignantlesions of the skin such as keloids. This inability to treat superficiallesions is due to the nature of the differential dose deposited at depthwith MV energy x-rays; these x-rays deliver a much lower dose within mmto cm of the surface than they do at depth due to the buildup of dosefrom scattered electrons as the beam passes through tissue. Thus it isdifficult to deliver enough dose near the skin surface withoutoverdosing tissue lying under the skin.

MV delivery systems also may not be applicable for use in the treatmentof tumors that receive radiation therapy at the time of surgery. Calledintraoperative radiation therapy (IORT), this special technique permitsthe application of a high dose of radiation during surgery. Thepossibility of manually moving healthy organs situated in between of theradiation beam and the target out of the beam path reduces the toxicityof the therapy. In addition, the possibility of directly visualizing thearea of intervention improves the degree of precision inherent in theadministration of the radiation dose. IORT offers several advantages: itmay eliminate post-surgery residual tumor; offer an intensification ofthe antitumoral effect of the radiotherapy in that it permits theadministration of a higher dose of radiation than would otherwise bepossible with external beam irradiation; reduce the time lapse betweenthe surgical removal and the irradiation, a period of time during whichresidual cellular clones can grow.

Intraoperative Radiation Therapy

IORT ideally should be given in the operating room (“OR”). However,conventional MV radiation equipment is very heavy and large and requiresthick concrete walls to contain the stray radiation produced by theequipment. This has restricted OR-based IORT to a handful of hospitalsthat have been able to absorb the high costs associated with theequipment and the construction of large shielded room in the OR. Mostother hospitals throughout the world that conduct IORT do so byperforming the operation in the OR and then transporting the patient,still under anesthesia and with the surgical site open, to the radiationfacility for the radiation portion of their treatment. After theradiation treatment is completed, the patient is then transported backto the OR for the completion of the operation. This method of IORTinvolves very complex logistics, increases patient risk, severely limitsthe number of patients that can be treated, and reduces the potentialefficacy of the treatment.

Other Approaches

MV devices have a range of other problems as well. Ranging in price from$1 M to in excess of $4 M depending on features, external beammegavoltage delivery devices are very complicated to build and are quitetime consuming when it comes to creating a plan for delivering thetreatment and in actually delivering the treatment. They require verycontrolled environments (temperature, power, and humidity) in which tooperate and must be installed in specially designed and shielded roomsin order to protect personnel from stray radiation. They requireconstant and expensive maintenance and monitoring, suffer fromsignificant downtime, and only can be used by highly trained personnelworking in dedicated departments.

As a result, a variety of techniques have been developed or are beingexplored to improve the delivery of a tumorcidal dose of radiation tosuperficial lesions either in an outpatient or intraoperative setting.Electrons, rather than x-rays, can be used for superficial skintreatments. Generated by the same megavoltage machines as x-rays,electrons pass less deeply into tissue and therefore have been used totreat superficial lesions. Electrons also can be used to deliverradiation to a tumor bed while the patient is undergoing surgery.Recently mobile IORT treatment units have been developed that can beused directly in an OR. These units are electron-based, and thereforerequire minimal shielding. Because the treatment is delivered in the ORthe biological effectiveness of the treatment should be improved throughtheir use.

Their major disadvantages are that they are not as easy to characterizeand plan for as are photons and they add cost to the price of thealready expensive MV device (which is used to generate them). They alsohave limitations when used to treat lesions that are directly under theskin surface. In terms of IORT, although much more mobile and userfriendly than their predecessors, mobile electron units still weighclose to one ton and are large and ungainly, making it difficult to movethem around in an OR and bring them in opposition to the treatment site,and are expensive in terms of user and patient time. They also arerelatively imprecise in terms of their ability to treat irregularlyshaped tumors and are quite time-consuming to plan for and use.

Low Energy Therapeutic Radiation

Kilovoltage x-ray units and orthovoltage devices also have been used totreat superficial tumors and other abnormalities. Whereas MV devicesdeliver x-rays with an energy of 1 MV to 20 or more MV, superficialmachines deliver kilovoltage (KV) x-rays with an energy of about 20-80KV (orthovoltage machines operate at 150-400 KV). These devices are lowcost, easy to build, and can be made very compact (with a tube as smallas several mm in diameter). In addition, they can be used easily andcheaply to image the patient at the same time the patient is beingtreated, allowing localization of the target and monitoring of theimpact of treatment. Because they are low energy they require verylittle in the way of user and patient shielding, making them able to beinstalled in almost any environment, increasing safety and reducingsignificantly the cost of building a treatment facility.

The major downside to low energy x-rays that has limited severely theiruse in modern day cancer treatment is that they have very poorpenetration in tissue. Superficial machines are designed to treat to adepth of 1-3 mm and orthovoltage machines to a depth of 3-20 mm (bothranges depend on energy). They have also a surface dose that is as muchas a hundred times more than the dose at depth resulting in thepotential for severe skin reactions when treating deeper lesions. As aresult therapeutic low energy x-rays delivered by traditional means arevery limited in their applications.

One approach that has been explored for improving this situation is todeliver the low energy x-rays in a rotational fashion such as with a CTscanner. When an x-ray source is rotated about the target with thetarget at the center of rotation, different portions of the skin aresubjected to the x-ray beam as it is directed to the isocenter. Thiskeeps the overall skin dosage at any one location relatively lowcompared to the concentrated dose at the target. This approach has beenexplored for use in radiosurgical treatments but is severely limited forsuperficial applications. Rotational treatments are only as good as theextent of the angle of rotation—the greater the solid angle of rotation,the greater the range of delivery positions of the x-rays relative tothe position of the target, thus the greater the dose at depth and thelower the skin dose. The best results are achieved when the x-rays canbe rotated through as many as 360 degrees or more. Unfortunately,because the depth of penetration of KV x-rays is so poor, there arelimited geometries that can be used through which to rotate the beam forsuperficial target locations, resulting in only several degrees ofrotation and therefore very little increase in dose at depth or loweringof skin dose.

Another approach that has been used to improve the effectiveness of KVx-rays involves the use of optically focused beams. A series of mirrorsare used to redirect KV x-rays such that they are concentrated in a spotat depth in tissue. By so doing, the dose to skin is reduced, the depthat which dose is possible is increased, and the rate at which dose isdeposited at depth is increased. Perhaps as important for very smalllesions, the dose falloff can be very sharp at the edges of thetreatment field. Effective at achieving the desired goals, this approachrequires the construction of a complex focusing system. Although suchcan be designed as an add-on device to an existing orthovoltage systems,it increases the cost very significantly and prices it out of the reachof practicing physicians. It also is quite inefficient, as the reductionin skin dose and the increase in treatment depth and dose rate at depthare achieved by concentrating the x-ray beam at a very small spot, thegains being proportional to the decrease in spot size. Thus largerlesions would need to be treated by scanning the spot across the target,achieved either by moving the patient under the delivery device or bymounting the delivery device in such a manner that the spot can bescanned over an immobilized patient; either approach adds considerablyto the cost of the overall system. When this is performed, the approachalso looses much of its sharp dose fall-off at the beam edges. Inaddition, it is not meant to treat superficial lesions; the process offocusing the dose would result in a potential increase in skin dose ifthe treatment were delivered to a superficial location. Finally, thissystem, like all other radiation therapy systems, requires extensivepreplanning and control over patient position in order to insure thatthe correct dose is delivered to the correct location within thepatient.

Devices for delivering low energy x-rays also can be inserted directlyinto the region in question in order to deliver a turmorcidal dose, orcan be delivered to a deep location by a needle that is delivered to thetumor by percutaneous puncture or by passage through a lumen or hollowviscus. This approach also is plagued by the problems inherent to datein using low energy x-rays, namely the dose where the x-ray beam firstenters tissue at the center of the volume being treated is very muchgreater than the dose in the rest of volume being treated. Attempts havebeen made to mitigate this problem by using multiple electronic x-raysources or multiple positions of a single x-ray source but thisincreases the invasiveness of the procedure.

Radioactive isotopes also can be used to treat deep volumes and can beused as well to treat superficial lesions and to treat the cavityexposed at the time of surgical resection. This can be done by shieldingthe isotope to control the direction in which the radiation is deliveredand then passing the isotope through channels contained in a matrix thatis laid on the skin surface or in the resection cavity. However, theproblem with radioactive isotopes is the same as with KV or low energyradiation—the dose is very much higher at the point(s) where the doseenters the tissue than at any other place. This makes it very difficultto deliver a uniform dose to a thickness of tissue or to deliver a doseat depth that is greater than the dose delivered to the tissue surface.

Target Identification

There also are problems associated with defining the region to betreated and to making sure that the correct region is treated.Typically, patients are imaged with CT or MR or ultrasound in order toidentify the target volume. The images generated from these proceduresare usually transferred into a treatment planning system where thetarget volume is outlined. It is then required that the patient positionat the time of treatment be registered to the patient position at thetime of imaging so that the treatment plan, created for a target volumespatially defined based on the patient position at the time of imaging,is correct based on the patient position at the time of treatment. Thisis a process that, because of its complexity and the difficulty inpositioning patients, is prone to error.

Need

Thus what is needed is a low cost system using low energy radiation thatcan treat regions of tissue of variable depth in a range of locations ina patient, such as regions on or below the surface of tissue, in acavity and the underlying region created following a surgical resection,on or below the surface of an internal cavity, hollow viscus, or lumen,or deep in tissue adjacent to an inserted probe or conduit or catheter,by delivering a dose at depth that is equal to or greater than the doseat the point of radiation emission without the need to preimage thepatient or preplan the treatment and in an automatic fashion such thatthe practitioner is released from the requirement of guiding anddelivering the treatment in a manual fashion, thereby improving accuracyand outcome, increasing the access of patients to such treatment, anddecreasing the risk to the user.

Targets Deep to the Delivery Device

The Need

In addition to the need for new apparatus and methods for treatingsuperficial lesions or lesions in close proximity to the radiationdelivery device there also is a need for new apparatus and methods whentreating tumors that are deep to the tissue surface or that are notaccessible by a needle or that are disseminated diffusely in tissue. Thetheoretical goal of any intervention for cancer, especially for suchtumors, is to eliminate malignant cells without effecting normal tissue.This is only theoretical because all known therapies have side effectsthat limit their usefulness. This is especially the case for radiationtherapy.

It is well known that any cancer cell can be killed if subjected to ahigh enough single dose of radiation. Such single session treatmentsalso are attractive to patients because if the limited amount of timethey need to spend receiving treatment. A specialized radiation therapydelivery technique called radiosurgery has been developed so that thedose that can be delivered to deep targets can be increased such thatcertain targets can in fact be treated in a single session. This isaccomplished by moving the x-ray source patient; a series of exposuresin which the beam is aimed at the tumor from different directions,including a series of rotational arcs, will keep a high dose on thetumor while spreading dose to healthy tissue over a much larger volume,significantly reducing dose to the healthy tissue.

However, because this single dose of radiation also will kill allsurrounding and interwoven normal cells within the treatment field, itis limited currently in the types of tumors it can treat. Also, itscost, believed to cost in excess of $5 M for equipment, room, andspecialized supporting infrastructure, limits its availability. As aresult of the clinical and limited access issues, most radiation therapyis delivered using a large number of small doses (fractions). Thisapproach is less effective (in terms of malignant cell kill) and takesmore time (multiple treatments over weeks versus a single treatment on asingle day) but is safer (in terms of normal tissue function) becausenormal cells receive less dose per treatment. Since normal cellseffectively are marginally less affected by radiation than malignantcells, the cumulative effect of the radiation over time is to destroycancer cells while allowing normal cells to continue to function.

Unfortunately, the marginal difference between the effect of radiationon malignant cells and normal cells is not great enough to allowradiation to be delivered to both regions indiscriminately, even withfractionation without incurring serious side effects. As a result muchtime and effort has gone into designing equipment and creating deliverytechniques that allow the greatest possible physical separation betweennormal and malignant cells so that the normal cells will receive lessradiation than the malignant cells. The most modern of these techniques(intensity modulated radiation therapy (IMRT), image guided radiationtherapy (IGRT), high dose rate remote afterloader brachytherapy) try toconform the high dose of radiation to the region of malignant diseasewhile avoiding delivering dose to as much normal tissue as possible.

However, modern day radiation therapy may have reached its limit interms of its ability to eliminate or control cancer, especially forinvasive cancers where the malignant cells intermix with normal cellssuch that killing the former also will kill the latter. Even with IMRTit is impossible to create a conformal enough dose distribution suchthat all cancer cells are destroyed but all normal cells are spared.IGRT reduces the amount of normal tissue that is included in thetreatment volume but cannot eliminate it entirely. Although metabolicimaging techniques can provide additional information about cancerlocation, the designation of a target volume is still a physician-basedprocess, fraught with inter- and intra-user variability and with aninability to differentiate disease from normal at the cellular level. Inaddition, many cancers contain radioresistant regions in their centerdue to poor oxygenation. It is not until the surrounding well oxygenatedcells are destroyed that oxygen can be delivered to the interior,thereby making these cells more radiosensitive. However, the amount ofradiation required to kill the initial group of oxygenated cells uses upall of the normal tissue reserve; the interior cells once oxygenatedcannot be treated with additional radiation without destroying surroundnormal tissue.

Thus it is possible that without a paradigm shift in the way radiationtherapy is delivered the physician-defined target-directed radiationtherapy of today probably is nearing its maximum capability as acancer-fighting therapy.

Binary Therapy

The limited efficacy and extended toxicity of traditional single agentcytotoxic therapy such as radiation therapy has led researchers toexplore the design and development of targeted binary therapies thatdifferentiate between, and thereby augment the effect on, malignantcells as compared to nonmalignant cells. A binary therapy is an approachthat utilizes two agents, each of which by itself has no cytotoxicitybut when used in concert become tumorcidal. In theory, if one or both ofthe two agents can be restricted to the cancerous cells only, then thetherapy can have an extremely high therapeutic ratio (ratio of dosedelivered to tumor versus dose delivered to tissue) with much lesstoxicity than conventional therapies.

A number of binary therapies are under development; those based on orincluding the use of radiation often are called radiogenic therapy.Although external beam MV radiation is being explored as a means ofactivating chemotherapeutic agents (an inactive “prodrug” is convertedto an active drug by the MV radiation) or gene vectors (an antitumor“pro-gene” injected into the tumor is converted to an active gene by MVradiation), it is believed that one of the more promising approaches isbased on the principle of dose enhancement through Auger electronemission.

When an x-ray encounters an atom, it interacts through one of threeprocesses: photoelectric absorption, elastic scattering, or Comptonscattering. The relative probability of each interaction is a functionof the x-ray photon energy. In Compton scattering, an incident photonloses enough of its energy to an outer orbital electron to cause itsejection. This electron has an energy equal to that lost by the photonas a result of the interaction, and can be quite sizeable. The originalphoton continues on its way but in a new direction, with a lower energy,and with the potential to interact again at any distance. Comptonscattering is thought to be the principal absorption mechanism forx-rays in the normal therapeutic range of 100 KeV to 10 MeV (millionelectron volts) and is relatively independent of the atomic number ofthe absorbing material.

The photoelectric effect is the most efficient means for conversion ofx-ray energy to ionization in the body and is believed to dominate atlow energy (10-120 KeV). It is a process whereby a photon, of an energynear the absorption energy of an inner electron shell in the targetmaterial, transfers its entire energy to the electron that subsequentlyis ejected from the atom (photoelectron). The relatively low kineticenergy of the ejected photoelectron is equal to the incident X-rayphoton energy minus the binding energy of the electron. The vacancy inthe electron orbital resulting from the electron ejection is filled byan electron from an outer orbit (with a lower binding energy), leaving avacancy in this outer orbit that in turn is filled by another electronfrom an orbit even further away from the nucleus. The surplus energyliberated when an electron drops from an outer shell to a shell closerto the nucleus results either in the emission of a fluorescent photon orin the ejection of an additional secondary electron (Auger electron)from the same shell. If Auger electron emission occurs, the atom is leftin a doubly ionized state (due to two ejected electrons) that isresolved by the dropping of other electrons from outer shells to fillthe holes. This cascade process results in the release of a large numberof very low energy electrons that travel very short distances anddeposit their energy (track ends) locally (therefore with a very highlinear energy transfer (LET)). If the electrons are produced near theDNA they can be very effective in killing the cell through double strandbreaks.

The depth of penetration of Auger electrons is very small, on the orderof 1-10 micrometers. Thus reliable cell death requires that the Augerelectron be generated within 1-10 micrometers of the DNA, e.g. withinthe cell (and preferably within the nucleus) itself The disadvantage ofthis approach is that the process for generating the Auger electronsmust take place within the cell. The advantage is that the tumorcidaleffect of the radiation is limited to the target cells. As a result,such a therapy has the potential for repetitive dosing with minimaltoxicity.

Dose Enhancement

Auger electrons at a target site can be increased significantly if ahigh Z material is introduced into the target as long as the energy ofthe radiation is at or near the K, L, or M electron shell bindingenergies for the high Z material. The radiation interacts with the highZ material that, because of the energy match between the radiation beamand the material's greater density of electrons (as compared to tissue),produces auger electrons in great numbers. This process is known as doseenhancement; the local deposition of dose is increased due to thepresence of a high z material. Dose enhancement with high Z materials isminimal or absent at high radiation energies because of the limitednumber of photoelectric interactions that occur at megavoltage energiesdue to the fact that the binding energy of high Z materials are in thelow energy range.

Depending on the element, concentration of element, and low energyphotons used, the local dose may be increased by as much as 150 fold ormore. Contrast material has been used traditionally as the doseenhancement agent in conjunction with orthovoltage x-rays in order toproduce an increase in the level of dose by a factor of 0.5 to as muchas 2 or more depending on energy and concentration of agent in thetissue (the higher the concentration, the greater the dose enhancement).Contrast agents contain typically a large percentage of a heavy elementfrom the upper half of the periodic table such as iodine or gadolinium;it is the interaction of the othovoltage x-rays with the element thatresults in the dose enhancement. Because tumors usually contain “leaky”blood vessels, contrast material injected in the vascular system willfind its way into a tumor through extravasation from these bloodvessels. In fact historically, it is the region of contrast enhancementthat is designated as the target volume for radiation therapytreatments.

It is important to note that contrast agents identify regions ofdisruption of vascular and by extension indirectly identify regions thatmay contain cancer cells. However, these agents do not identify cancercells directly. Thus by using a contrast agent alone to generate doseenhancement, it is possible not only to kill normal cells containedwithin the region of contrast enhancement but to not identify cancercells that lie in regions that do not enhance, or where theconcentration of cancer cells is too small to cause vascular disruption.In addition, it is often difficult to deliver enough contrast agent tothe region in question by the IV route in order to achieve significantenough dose enhancement. Direct injection allows for a higherconcentration of contrast agent, but it requires an invasive procedurethat may not gain access to all tumors.

There are other materials that have been explored for dose enhancementwith radiation of all types, namely gold particles of any size, andother ways of delivering the particles to the tumor so that onlyabnormal cells are labeled or are labeled preferentially, namely usingantibodies, oligonucleotides, nucleotide analogues, amino acids, anddendrimers. Gold nanoparticles are inert and biocompatible and the goldsurface provides a simple chemistry for the self-assembly to labelingmaterials thereby encouraging the nanoparticles to accumulate in thevicinity of, or directly inside, malignant cells. They can be deliveredby IV injection or sprayed/injected directly onto/into the target (ifaccessible) and can accumulate in concentrations sufficient to blanketall cells in the target volume. Gold nanoparticles, when used in thepresence of 50 kvp radiation, are predicted to result in a doseenhancement of as much as 150 fold based upon published studiesperformed with thin gold foil. However, the actual enhancement able tobe obtained in a clinical setting is dependent on the percent of thetotal mass contributed by the gold. With reasonable levels of 0.3-3%that are obtainable clinically, an enhancement level believed to be onthe order of 2-10 fold can be expected.

The differential dose enhancement of tumor cells versus normal tissueonly occurs if the high Z material is linked to tumor cells and not tonormal cells. Means for achieving such in the past have centered on theuse of contrast agents; the agent leaks out of highly permeablevasculature in the tumor to stain the tumor and not surrounding normaltissue possessing normal vessels. However, ideally one would like totarget the tumor cells directly, thereby allowing direct differentiationbetween normal and abnormal cells. Since the enhanced effect from Augerelectrons are believed to occur predominantly in the cells where theyare generated, direct targeting of abnormal cells could allow thedestruction of an abnormal cell while sparing an immediately adjacentnormal cell.

Problems with Low Energy Radiation

The major downside to low energy x-rays that limits their use in doseenhancement applications is their very poor penetration in tissue asdescribed previously. At a depth of 20-30 cm, the residual dose from a50-70 KV beam, the optimal energy range for gold dose enhancement, isabout 0.001-0.1% of its maximum dose; even at a maximal 10× enhancementno more than 1% of the maximum dose at the surface will be delivered atdepth. This can be improved by using multiple fields to deliver thetreatment, such as is used in radiosurgery, thereby spreading the doseto nontarget tissue out over a larger area. However, even using 10fields will only result in a dose at depth that is at best equal to 10%of the dose at the skin.

A range of approaches such as optically focused beams and rotationalx-ray sources have been used to increase the dose of low energyradiation deposited in deep targets that would interact with doseenhancement agents; these were described previously. Unfortunately, thesame problems discussed previously that apply to each of the low energyx-ray delivery approaches without the use of dose enhancement apply totheir use with dose enhancement, namely a high cost, complexity, a lackof portability, lengthy treatment times, and limited availablegeometries restricting applicability, apply when used with doseenhancement. Another approach that has been explored is with the use ofa monenergetic beam of radiation produced by a synchrotron that is ableto deliver the required radiation at a much faster rate. Unfortunately,this is a $100 million device based on a cyclotron that limits severelyits availability and suitability.

Thus there still is a need to develop a realistic, practical, cost andtime efficient, portable, universally available, easy to manufacture,and easy to use means of delivering in a single or few fractions tocancer cells deep in a patient a dose of radiation sufficient enough tobe able to benefit from the dose enhancement possible with high zmaterials delivered selectively to the target without producing too muchdose of radiation in other portions of the patient and especially at thetissue surface.

SUMMARY

This present invention provides methods and apparatuses for performingradiation therapy with low energy x-rays on a selected region of tissuein a patient in proximity to the apparatus whereby the amount ofradiation delivered to the region can be equal to or greater than thedose delivered to the tissue or other material through which theradiation passes. It also provides methods and apparatuses for fullyautomating the process, from treatment region identification throughtreatment planning to treatment delivery, and can be used to treatregions on or below the surface of tissue, in a cavity and underlyingregion created following a surgical resection, on or below the surfaceof an internal cavity, hollow viscus, or lumen, or deep in tissueadjacent to an inserted probe or conduit or catheter.

The preferred embodiment employs a small tabletop stationary five-degreeof freedom device such as a “robot” that is used to define the treatmentregion by tracing the region under direct visualization and then toprecisely deliver the treatment plan created by an automatic planningsystem by positioning a single low energy radiation source, or aplurality of low energy sources connected to each other in apredetermined parallel or similar geometry, each of which may beequipped with blocking and attenuation mechanisms, at a plurality ofpositions in a planar fashion across or through a selected treatmentfield, thereby delivering a plurality of parallel overlapping beamsindexed on a millimeter or submillimeter grid such that a concentrationof dose is achieved at a variable depth in tissue relative to the dosewhere the radiation first enters the tissue.

The present invention also provides methods and apparatuses for creatingwith low energy x-rays a high dose of ionizing radiation in unhealthytissue, such as tumors, at any depth while maintaining low dose in allother healthy tissue regardless of its location. The method employs theuse of low energy radiation delivered at a high enough dose at any depthsuch that sufficient secondary radiation can be generated through theuse of dose enhancement agents such as nanoparticle gold such that acomplete tumorcidal dose of radiation can be delivered in as little as asingle treatment session without damage to any nontumor tissue. Thepreferred embodiment employs a scanning beam electron device, includingmeans for attenuating and blocking the beams of radiation, used togenerate a plurality of overlapping beams indexed on a millimeter orsubmillimeter grid that converge on a target volume loaded with goldnanoparticles, thereby delivering a tumorcidal dose of radiation totumor cells but not to normal cells within or outside the treatmentvolume.

Objects and Advantages

The benefits of this invention are many. These include:

-   (a) the ability to create a range of depth dose curves using a low    energy source such that a range of lesions of different thickness in    close proximity to the radiation source can be treated;-   (b) the ability to create depth dose curves using a low energy    source where the dose at depth in tissue can be greater than the    dose at entrance into tissue if desired or where the dose at depth    can be the same as the dose at entrance into tissue;-   (c) the automatic nature of the planning process for delivering such    a dose, thereby eliminating the need for preplanning the treatment;-   (d) the real-time patient-based nature of the target definition,    thereby eliminating or reducing the need for, and error associated    with, preimaging and delineation of the target in software;-   (e) the automatic delivery nature of the dose, thereby eliminating    the need for the user to be at the patient side when the treatment    is delivered, thus reducing issues associated with shielding the    user from radiation;-   (f) the precise nature of the treatment delivery, thereby    potentially improving outcome.

Further benefits and advantages of this invention include:

-   (a) the ability to deliver a tumorcidal dose of radiation to a    target volume not in close proximity to the radiation source without    delivering significant dose to nontarget tissue regardless of its    location;-   (b) the ability to vary the depth at which dose is delivered by    varying either the energy used to deliver the treatment or the focal    point of the treatment, whichever is more appropriate given the    clinical conditions;-   (c) the ability to differentiate normal from abnormal tissue within    a targeted treatment volume and to use that differentiation to    effect different levels of radiation.

This invention will allow targets in close proximity to the radiationsource, such as the skin, operative cavity, lumen of a hollow viscusvessel, or deep target accessed by a catheter, to be treated in highlyprecise and tailored manner regardless of their location. Furthermorethe combination of a low energy delivery device delivering increaseddose at depth and nanoparticle dose enhancement will allow all tumorsregardless of depth or location to be treated to a very high dose in asingle or few sessions without incurring damage in surrounding normaltissue or overlying skin. It will eliminate the need to worry aboutminor patient movement during treatment and reduce the complexity ofequipment used to deliver radiation therapy treatments. It also willallow such a treatment to be delivered with relatively low costequipment in an outpatient setting with minimal if any radiationshielding. Furthermore, it will allow noncancerous cells within a tumorto be spared and will allow cancerous cells outside of a localized tumorto be destroyed without damaging the tissue within which they reside.

In summary, the apparatus and methods disclosed will allow low energyradiation to be used in a much greater range of clinical applicationsthan would otherwise possible.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A to 1D show normal depth dose curves from a KV x-ray sourcedisposed in typical treatment scenarios.

FIG. 2A to 2D show normal depth dose curves from a KV x-ray sourcedisposed with multiple beams to cover a large target.

FIG. 3A to 3B show the depth dose curves from a KV source with variableattenuation.

FIG. 4A to 4C shows a means for producing variable attenuation orhardening and resulting sample depth dose curves.

FIG. 5 shows an alternative means for producing variable attenuation.

FIG. 6 shows an alternative means for producing fixed attenuation.

FIG. 7A to 7F shows means for producing variable beam blocking orshaping or collimation.

FIG. 8 shows an alternative means for producing variable beam blockingor shaping or collimation.

FIG. 9 shows an alternative means for producing beam blocking or shapingor collimation.

FIG. 10A-D shows the delivery geometry for the preferred embodiment.

FIG. 11A-C shows a treatment probe inserted into a body cavity and theresulting delivery and depth dose curves.

FIG. 12A-C shows a treatment probe inserted into a body cavity with amodified delivery geometry.

FIG. 13 shows examples of depth dose curves resulting from the use ofthis invention.

FIG. 14 shows a means for producing indexed beams of radiation.

FIG. 15 shows a means for grouping radiation sources together to produceindexed beams of radiation.

FIGS. 16 a to 16 b shows two views of an alternative means for producingthe desired result using a scanning electron beam instead of a fixedx-ray source.

FIG. 17A to 17B shows two views of an alternative means for producingindexed beams of radiation used to treat the surface of a patient orcavity.

FIG. 18 shows the flow diagram for using this invention.

FIG. 19A to 19B shows a means for defining and capturing electronicallythe region to be treated.

FIG. 20A to 20D shows a graphical tool for inputting required deliveryinformation.

FIG. 21A to 21B shows a means for determining if the treatment regionhas moved once data has been acquired.

FIG. 22 shows an alternative means for determining if the treatmentregion has moved once data has been acquired.

FIG. 23A to 23C shows a mean for variable collimating an array oftreatment beams.

FIG. 24A to 24B shows parallel and convergent delivery geometries asapplied to a scanning electron beam device.

FIG. 25A to 25C shows collimator plates formed to generate differentshaped and directed beams of radiation.

FIG. 26A to 26D shows using a parallel plate design to deliverconvergent beams.

FIG. 27A-27D shows a variable collimator design modified to deliverconvergent beams.

FIG. 28A to 28C shows depth dose curves for different half-value layersfor different delivery scenarios: FIG. 28A is for unmodified kvp beams;FIG. 28B is for modified kvp beams to a 4 cm target; FIG. 28C is formodified kvp beams to a 10 cm target.

FIG. 29A to FIG. 29B shows varying depth of treatment by varyingposition of beam array.

FIG. 30A to 30C shows the delivery of multiple fields spaced around apatient.

FIG. 31 shows depth dose curves using multiple fields with the currentinvention.

FIG. 32A to FIG. 32C shows multiple sizes, shapes, constructs ofnanoparticles.

FIG. 33 shows depth dose curves using energy modulation to adjust fortarget depth coupled with dose enhancement and multiple fields with thecurrent invention.

FIG. 34 shows depth dose curves using range modulation to adjust fortarget depth coupled with dose enhancement and multiple fields with thecurrent invention.

FIG. 35A to FIG. 35C shows using treatment beam to image patient andtarget.

DETAILED DESCRIPTION OF THE INVENTION Targets in Proximity to TreatmentDevice

In the preferred embodiment a low energy x-ray tube with an energyranging from 20 KV to 120 KV that is as small as 1 mm or less indiameter can be used as the source of radiation. Such tubes have beendescribed by many and are now in commercial production. Radioactivesources of radiation or larger x-ray tubes also can also used with anappropriate increase in the size of all other components to bedescribed, although as the size of the radiation source constructincreases, the fewer are the areas that can be reached by the constructdue to collision between the construct and the surrounding anatomy. The% dose versus depth in tissue curve from low energy x-rays 321 in FIG.1B along the plane 326 in FIG. 1A delivered from such a low energyradiation source 322 that spreads 323 and is impingent on a target 324in a patient 325 does not fall off in a pure exponential manner as isthe case with megavoltage (MV) x-rays. Much of the beam that is emittedby such a small kvp x-ray device consists of very low dose photons thatare attenuated very rapidly in very small thicknesses of tissue.Therefore an increased amount of dose is deposited at or very near theskin surface when compared to filtered KV devices or MV devices. It isthis increased deposition at skin surface that in part makes low energyradiation difficult to use in many treatment applications. It is alsothe fact that because of the low energy even filtered KV beams do notpenetrate very deep in tissue. This is the case whether the beam ofradiation is emitted from the end of the source 323 in FIG. 1A orcircumferentially 327 in FIG. 1C around the source producing curve 329in FIG. 1D along plane 328 in patient 325 in FIG. 1C. Targets thatrequire the overlap of more than one beam simply to achieve coverage oftargets that are greater than the size of a single beam are stillplagued by this same problem, as shown by curve 31 in FIG. 2B alongplane 32 in FIG. 2A and curve 33 in FIG. 2D along plane 34 in FIG. 2C.

Attenuation

The magnitude of this problem can be reduced by interposing a variablethickness of attenuating (also known as filtering or hardening) material36 between the x-ray source 37 and the patient 38 in FIG. 3B such thatbeam hardening can occur. By filtering out much of the very low energyx-rays prior to the beam interacting with tissue, the shape of thecurves 39 in FIG. 3A showing % dose versus depth for different thicknessof attenuation once the beam enters the tissue become less steep andtherefore the dose at the surface relative to the dose at depth isreduced. In essence, as the amount of attenuation material is increasedthe beam becomes more and more like a monoenergetic beam that has a trueexponential depth dose curve.

The thickness of the attenuating material secured to the radiationsource can be varied by several means. The preferred means involves theuse of a device whereby the amount of attenuation can be varied, such asthe small bellows 40 in FIG. 4A and FIG. 4B filled with water or someother attenuation material that is fitted to the end of the radiationtube 41: the higher the attenuation or the density of the material thebetter; for instance mercury or some other flowable high densitymaterial such as a tungsten slurry is ideal. By varying the length ofthe bellows while keeping it filled with the chosen material by drawingit from a reservoir 42, the amount of attenuation between the beam andthe patient can be varied very finely, producing the curves for one mmof water attenuation 43 for instance and 44 for four mm attenuation. Theeffective attenuation that is preferred is the equivalent of anywherefrom 1-5 mm of tissue. By using a high attenuation material thethickness required to achieve this amount of effective attenuation canbe reduced to less than 0.1 mm equivalent per mm of tissue.

In this embodiment, the bellows is made of a material that will notdegrade in the presence of low energy radiation, such as mylar or a thinlow density metal. The bellows is filled from a pressurized reservoir.Bellows length can be changed by increasing/decreasing pressure in thereservoir after the pressure/length ratio has been measuredexperimentally. Alternatively, the length can be changed by physicallypushing/pulling the end of the bellows through the use of small armsattached to the end of the bellows, the length controlled by monitoringthe change in length of the arms through potentiometers attached to themotors driving the arms or through other suitable means. In addition, ifthe lengths are changed asymmetrically, a wedge type distribution can becreated.

In another embodiment, the attenuation can be provided by a range ofsmall caps 56 made of attenuation material that fit over the end of thex-ray tube 55 as in FIG. 5. These caps can be secured manually by theuser or can be selected automatically by the small robot described inFIG. 14 using a “pluck and play” mechanism similar to that used bycomputer-controlled milling machines. Each cap would have a differentthickness of the same material or the same thickness of differentmaterials such that, by choosing the appropriate cap, the desiredattenuation can be achieved. Any other means for varying the thicknessof material at the end of the tube can be used as well. In addition,attenuation can be achieved by laying a piece of attenuating material 68in FIG. 6 over the region in question 69 so that the radiation beam 67passes through the material prior to entering the tissue overlying theregion to be treated.

Collimation

The amount of spread of the radiation beam also must be controlled asthis determines how much tissue a beam will hit as it passes through thepatient or conversely how much tissue a beam is able to cover. A varietyof different beam shaping devices have been created in the past and canbe used in miniature form with the small x-ray tube that is part of thepreferred embodiment of this invention. For such a small beam, FIG. 7depicts beam shaping accomplished in one of two general manners; thebeam shaping material 71 can be lengthened/shortened relative to the endof the radiation source by moving it closer to or farther from the endof the radiation source or the opening formed by the beam shapingmaterial 73 can be increased or decreased. Either approach can be usedwith this invention and will change the amount of beam spread 72. Theformer can be implemented as in FIG. 8 by using a cylindrical housing orbellows 84 that is extendable and that is filled with a radioopaqueblocking material much in the manner used with the attenuator. Byextending the bellows, the length of the shaping material is increasedand limits the spread of the beam. It also can be implemented by fixedlength metal blocks that are raised and lowered by a mechanical linkagedriven by a motor. The latter approach can be implemented by pairs ofblocks of fixed height that are driven in/out through a linage attachedto a miniature motor, thereby changing the size of the opening betweenthe blocks and thus the beam spread. In addition, any other meanscommonly in practice can be used to shape the beam. Although it isdesired that the ability to change the spread of the beam be adjustableduring the course of treatment, blocking or beam shaping can beaccomplished in a non-variable manner as well. For instance, a sheet ofmaterial 95 that is opaque to the radiation beam and contains at leastone aperture 96 of known but variable size acting as radiationtransmissive can be laid over the surface of the region to be treated97. By having a range of sheets each with apertures of a specific size,different amounts of blocking can be implemented.

The use of a beam shaping device will control the spread of the beam andthe use of an attenuation device will change the speed of dose fall-off.However, the resultant depth dose curves will all be of the same generalshape for a single beam—greatest dose at the surface with dosedecreasing with depth—and will be fixed as a single curve for a givenenergy and amount of attenuation. These modifications or steps do notallow one to change the shape of the depth dose curve and the percentageof dose at depth to fit the clinical needs. An additional aspect of thepresent invention will allow the actual shape of the curve to be changedso that maximum dose can be deposited at a depth other than the surface,or over a larger distance, as determined by the requirement of thetreatment.

Disposing Beams in an Array

As mentioned previously, treating a volume of tissue in proximity to theradiation source located on or below the surface of the patient, in acavity and underlying region created following a surgical resection, onor below the surface of an internal cavity, hollow viscus, or lumen, ordeep in tissue surrounding an inserted probe or conduit or catheter,calls typically for covering the entire target with a single beam ofradiation if the volume is small or using several beams of radiationthat minimally overlap in order to cover the volume if it is large. Inthe present invention, a very large number of beams are used to coverthe target regardless of its size with no requirement that the entiretarget be covered by any given beam of radiation. Instead, increaseddose at depth is achieved by precisely indexing the beam 101 inmillimeter or submillimeter increments across the target 102 in patient103 as in FIG. 10A, with each portion of the target being covered by avery large number of beams.

Each beam will increase the region that it encompasses as it passesfarther from the source and deeper into tissue due to the spread of thebeam. As the beam spreads it will overlap with other beams to a greaterand greater degree. As the beams overlap the radiation contained in thebeams will add together, increasing the dose delivered to any given spotwithin the target volume relative to that received by a single beam. Atthe same time, the area of tissue at the point of beam entrance willreceive radiation from one or at most a few beams. This tendency for thetotal dose to increase with depth due to overlapping of beams iscounteracted by the tendency of the dose from any given single beam todecrease with depth as the beam is attenuated by the tissue throughwhich it is passing. Depending on the size and shape of the beam and thesize of the index distance, the amount of overlap will vary, with somegeometries resulting in an increase or a decrease in the number of beamsthat cover any given portion or all of the target (FIG. 10B). By varyingthe spread of the beam, the attenuation of the beam, and the spacingbetween or index of the beams, these two opposite tendencies can becontrolled in order to create different amounts of relative total dosedeposited at any given depth and therefore the shape of the depth dosecurve. As long as the number of beam overlaps increases with depth andnot at the tissue surface, the effect will be to reduce the amount ofdose at the tissue intercept surface relative to the amount of dose atdepth. In the preferred embodiment of the present invention each of themany beams of radiation is delivered from a planar indexed positionrelative to the first beam forming a one or more dimensional array ofbeams where all beams are parallel to each other (FIG. 10C). However,other pseudoparallel geometries are possible, such as one required totreat surgical cavities 104 in FIG. 10D where each beam 105 is directedorthogonal to the tissue surface through which it must pass, some ofsuch beams shown.

The actual index amount used to deliver a treatment will depend on anumber of factors including the size of the electron target that is thepart of the x-ray source used to generate photons, the shape, size, andamount of blocking used to configure the beam, the desired depth dosecurve, and the distance the radiation device is from the tissue surfacethrough which beams of radiation will be passing. In general, the indexamount will be one that causes the beams of radiation emitted by thesource to begin to overlap just at the tissue surface. Thus the indexamount will be greater for beams with a steep angle of spread then forbeams with a shallow angle of spread, will be greater for a deliverydevice that is removed from the tissue surface than for one that is indirect in contact with the tissue surface, and for a delivery devicewith a photon generating target of a millimeter or more than for onewith a submillimeter target (the larger the target, the wider is thepenumbra and therefore the greater is the effective beam spread).Regardless, the index amount given the normal range of radiation devicesfor which this invention is expected to be used is in the submillimeterto several millimeter range.

By adjusting simultaneously the amount of attenuation, the spread of thebeam, and the spacing of beams, it is possible to create a wide range ofdepth dose curves. In addition, by varying the beam energy, it ispossible to increase even further the range of depth dose curves thatcan be created (FIG. 13). This ability to vary the shape of the depthdose curve is of value for superficial and deep conditions alike, thesole criteria being a need to alter the delivery of radiation to thetarget volume from one where the dose when the radiation first enterstissue is very much higher than the dose at any distance from theradiation source to one where the dose at some distance from theradiation source is equal to or greater than the dose when the radiationfirst enters the tissue.

Medical Applications

There is a medical value in being able to vary the depth dose curve inthis manner. There are various superficial diseases that can benefitfrom radiation treatment that lie at different depths below the surfaceof the skin yet within the range of treatment possible with KV ororthovoltage radiation. For instance, some skin cancers requiretreatment only to a depth of several millimeters while more advanceddisease may require treatment at a deeper depth of a centimeter or more.With unmodified KV radiation, only a single depth dose curve is possiblewith maximum dose delivered to the skin: to deliver adequate dose atdepth will require delivering too much dose to the skin surface. Withthis invention, as can be seen in FIG. 13, a treatment dose can bedelivered from skin surface to as much as 1 cm deep by 133.

Alternatively, the maximum dose 131 can be moved below the surface to adepth of as much as five mm or more with skin sparing. As anotherexample, keloids are a condition that requires sufficient dose deliveredto the skin surface and at least two millimeters below the skin surface.With this invention, as seen with 132, dose is within an acceptablerange from the skin surface to this two mm depth and then falls offrapidly. For IORT applications, it is desired that dose be delivered tosome arbitrary depth is tissue below the surface of the exposed surgicalcavity. However, prior to this invention, if the dose at the immediatesurface is too high, the dose required at depth to destroy remainingcancer cells cannot be achieved without destroying tissue at thesurface. With the herein described approaches, it is possible to deliverdose at depth while not delivering an excessive amount of dose to thetissue surface.

In addition there are other applications where the treatment of smallvolumes of tissue cannot be achieved because the dose in the portion ofthe volume near the x-ray source is too great relative to the dose somedistance from the x-ray source. For instance, in FIG. 11A assume 2 mmradiation probe 109 is inserted in tissue volume 110. 112 describes thetypical spread of the dose that would result from a single position ofthe 2 mm x-ray source emitted from an active target region 111; the dosespread would be similar for a radioactive source. The depth dose curvealong 113 would look like 114 in FIG. 11B. It is possible to overlapmany beams with indexing as described herein and depicted in FIG. 11C.However, because the beams overlap at their origin as in region 113,there is no increase in dose at depth compared to the surface and thedepth dose curve along 116 would look the same as 114 in FIG. 11B.

If the electron target in the x-ray probe was reduced in size 121 inFIG. 12A and/or as in the preferred embodiment the beam was blocked soas to produce dose spread 122, the depth dose curve for a singleposition of the probe would still look like 113 in FIG. 11A. However, ifnow the beams are indexed as described herein there is overlap of beamsat depth but not at the surface 124 in FIG. 12B and curves such as 125and 126 in FIG. 12C are possible. This compares favorably to the curve127 that would result from normal delivery as is practiced routinelytoday.

Robot for Implementing Array

Since the degree of beam overlap is the primary determinant of thevariation in depth dose it is required that the beams be positionedprecisely so as to achieve the desired degree of beam overlap. Thepreferred means of implementing the indexing of the radiation source isachieved as in FIG. 14 by securing the small x-ray tube 141 to the armor attachment point of a small multiple degree-of-freedom manipulator ordevice 142 such as a table-top robot or a multiple-stagetranslational/rotational manipulator or device. This device allows thex-ray tube to be moved around with unlimited freedom but under computercontrol. It is required that the robot be able to translate the x-raytube over the surface of the region to be treated and to raise and lowerthe tube. It is desirable but not required that the device be able alsoto angulate the tube relative to the region to be treated as thisincreases the range of conditions that can be treated and the range ofdelivery geometries that can used. It is also desirable but not requiredthat the x-ray tube be able to rotate around its central axis relativeto the region to be treated. In the preferred embodiment the smallmultiple degree-of-freedom manipulator or device 142 sits on a cart 143that includes also a display terminal 144 for interacting with thesystem as well as a place for attenuators (if caps are used), acomputer, a keyboard, and a power source. The cart has a locking systemto prevent the cart from being moved once treatment begins. The cart mayalso include the treatment planning computer and software as well as thelocalization system to be described below if this is separate ordifferent from the robot. At the time of treatment the robot willposition the x-ray tube over the region to be treated and, after thebeam is activated for the prescribed amount of time, will preciselyindex the position to the tube in order to deliver the next beam,repeated as required. If multiple x-rays tubes are used connectedtogether in a known geometry 153, then the robot will carry thisassembly and will index the assembly after the first beam-on time 152 sothat the resulting array of beam positions will meet the planrequirement (FIG. 15).

Scanning Electron Beam for Implementing Array

As noted a requirement of the system is that a larger number oftranslated beams overlap in increasing, known, and controllable amountsfrom a given beam direction as the beams penetrate deeper in tissue. Itis also possible to deliver indexed beams of radiation that meet theserequirements by other means. For instance, instead of attaching thex-ray tube to a robotic arm and using the robot to index the tube, thetube could be held still and the patient support device indexed. Anothermeans for realizing the same goal FIG. 16 is to use a scanning electronbeam device that scans a small electron beam 161 over an anode target ina predetermined pattern. The anode target has an at least aone-dimensional array of equally spaced targets 162 dispersed over itssolid surface 163. When the electron beam hits the target photons aregenerated. On the under side of the plate is adhered 164 a secondaryplate of beam blocking material that has at least a one-dimensionalarray of equally spaced apertures acting as x-ray transmissive passagesthrough the collimator corresponding in position to the targets 162. Onthe underside of the secondary plate 84 can be a tertiary plate made ofattenuation material 165. Each of the apertures is precision shaped suchthat a beam emitting from the target lying over the aperture iscollimated to create a beam 166 that spreads as it leaves the plate. Bycontrolling the thickness of the collimation plate and the shape of thehole, a pattern of beam overlaps can be created that is the same aswould be produced by the preferred embodiment described above. Thisentire apparatus can be secured to the end of a robot arm or c-arm orother positioning device so that it can be brought to overlie closelythe tissue surface to be treated.

Surface Guide for Implementing Array

An additional means for delivering precisely the indexed position of thebeams would include establishing a predetermined path laid down for aradiation delivering catheter to follow that involves effectivelycreating variable indexing of catheter position in at least twodirections or multiple catheters in at least one direction and wheremeans are provided for varying beam spread and beam attenuation. Forinstance, in FIG. 17 a grid 171 of tubes or channels 172 is created intowhich the radiation device 173 can be inserted. Each tube or channel iskeyed to the catheter containing the radiation device such that thedevice can be inserted into the channel in a known orientation that isconstant from channel to channel or tube to tube. The radiation tube canbe indexed along the length of the guide tube 172 using the robot orsome other linear indexing device such as a remote afterloading deviceused commonly with high dose radioactive sources or with commercialelectronic x-ray tubes. Under the grid is placed a pad 175 made up ofattenuation material through which the beams will pass. In thisapplication, the x-ray tube or radioactive source will need to beconfigured to shape the beam 176 through the use of a radiolucent windowor specifically constructed photon target, and the indexing in thedirection perpendicular to the length of the guide tube will bepredefined by the position of the guide tubes. Alternatively, acollimation plate can be laid on the tissue surface that has in it an atleast one dimensional array of apertures that can be used to collimatethe beam to meet the shape and index required to produce the desireddose distribution. In such an implementation, the device used toestablish the path of the radiation source would have shielding materialsurrounding it in all areas except the portion that comes in contactwith the tissue surface. In this manner collimated beams would bedelivered to the tissue while the rest of the patient or room in whichthe patient was being treated would be shielded from radiation.

Collimation System

A collimation system FIG. 23A-FIG. 23C has been designed for use withboth of these alternate embodiments. It comprises four plates of similarshape and design shown in FIG. 23A each of a thickness and materialappropriate for blocking the radiation beam by greater than 98%. Ideallythe plates are constructed of a very radiodense material such astungsten in order to keep the overall thickness of the collimation to assmall an amount as possible. Each plate comprises a lattice with aseries of strips of beam blocking material 236 alternating with stripsof no material 237. These plates are overlaid on top of each other in astacked fashion, two of the plates orthogonal to the other two, suchthat an at least one dimensional grid of transmissive openings arecreated FIG. 23B. The size of the openings can be varied in a continuousfashion by moving all four plates in by the same amount. This will causea uniform and equal decrease in the size of all of the openings as inFIG. 23C. Any means for driving the plates the appropriate distance canbe used.

Planning System and Target Definition

The determination of beam index is the most important determinant ofmodifying the depth dose curves. Although the use of variableattenuation and beam shaping is of significant value, it is possible tobenefit just from the ability to precisely implement a predetermined butvariable index amount, or any other combination of variable index andone or more of beam energy, beam attenuation, and beam blocking.

As indicated, there can be quite a few variables that will affect theresultant dose distribution, including but not limited to beamdivergence, beam attenuation, beam energy, and beam indexing. Thesevariables must be factored into the treatment planning process. It isdesirable that this planning process be automatic as possible and asfully integrated into the delivery system as possible. Therefore thepreferred embodiment includes also a means for generating a treatmentplan that will result in the correct dose delivery. Since as shown thedepth dose curve is sensitive to the amount of attenuation, beam spread,and beam index, the planning system must be able to determine thecorrect combination of values that will result in the desired depth dosecurve. In addition, the system must know what is the size and shape ofthe region to be treated.

The planning flow is diagramed in FIG. 18. The first step, afterimmobilizing the region to be treated as well as the delivery device, isto identify and delineate the region to be treated. The region can be onor below the surface of the patient, in a cavity and underlying regioncreated following a surgical resection, on or below the surface of aninternal cavity, hollow viscus, or lumen, or deep in tissue surroundingan inserted probe or conduit or catheter. The preferred embodiment forthis step of the process calls for acquiring directly off the patientthe shape and location of the region to be treated. This can be done bytracing, outlining, or painting over the area to be treated with alocalization system that then transfers this information to the planningsystem. In the preferred embodiment the robot, or a multiple degree offreedom device, that will be used to guide the delivery of the treatmentis used to acquire information directly from the patient regarding theregion to be treated. After immobilizing the patient and the robot nextto the patient, the robot is used in a passive data acquisition modewhereby the control system for the robot records the position of the tipof the arm in the coordinate system of the robot as the user guides therobot arm around the contour of the region to be treated or over thesurface of the region as if painting it with a paint brush. That is, theuser traces the region to be treated with the arm of the robot while thecontrol system records the movement of the arm and computes the locationof the tip of the arm as it is moving. This “recording” capability iscommon to many existent robot systems. Functionally, at the time oftreatment, the control system is put into a “data acquisition” mode,which automatically places the arm into this passive mode, and theregion to be treated is outlined by the user tracing it or “paintingover it” with the end of the arm. Although it is preferred that thedevice used to treat the patient is the same device used to acquireinformation about the region to be treated, it is possible to separatethese two tasks. Thus another means of acquiring the same data is to usethe cameras 191 of a camera localization system FIG. 19 to determine theposition of active or passive markers 192 placed on the robot arm or ona pen that is used by the user to trace the region of interest 195 in aplane perpendicular to the region 193 in FIG. 19A and looking down onthe region 194 in FIG. 19B. A magnetic localization system also could beused in place of the camera system as could any other means foracquiring 3-D data such as but not limited to a an infrared localizationsystem, a sound-based localization system, a laser scanning system, or alaser range finder system.

This 3-D information designating the spatial limits of the region to betreated is transferred automatically to the treatment planning systemfor plan generation as in FIG. 18. The depth and thickness of the regionto be treated is designated by the user by entering the appropriatevalues into the user interface of the planning system or by manipulatinga small graphic tool 201 in FIG. 20A displayed on a screen of the userinterface 200 of the planning system; the user both moves the toolaround on the display to define depth of desired dose (distance belowthe surface) and adjusts the size of the tool to indicate thickness ofregion to be treated. This allows the user to define a range of sizesand regions to be treated, such as 204 a thin lesion at the surface, 205a thin lesion below the surface, and 206 a thick lesion below thesurface. These two pieces of data, along with the shape and size andlocation of the region to be treated, as well as the desired dose towhich it should be treated, also entered by the user, are used by theon-board planning system to generate a treatment plan. The plan willdetermine automatically the best combination of index amount and dwelltime at each beam position, as well as beam energy, attenuation, andbeam shape if the delivery device can support these features, to achievethe desired treatment as according the flow in FIG. 18. Any number ofalgorithms can be used to generate the treatment plan based upon theentered data and the known effect the various variables have on theshape of the depth dose curves; this process is well known in the fieldof radiation therapy and is known as inverse treatment planning Ofcourse it is also possible to determine the treatment deliveryparameters by hand or in a manual “trial and error” process as is thecase with many approaches to treatment planning.

As noted, the planning process results in a set of delivery parametersthat includes at least beam positions and beam position dwell time andcan include the energy, attenuation factor, and beam shape. Afterreviewing the plan, the user approves the plan and then initiatestreatment. This sets the robot into delivery mode, selects the degree ofattenuation, energy, and beam shaping if such features are supported,and activates the x-ray tube. The robot then proceeds to deliver thetreatment under computer control until the entire target is treated tothe desired dose.

Treatment Monitoring

It is also possible to include the ability to terminate the treatmentshould the patient move during administration of the radiation asindicated in the flowchart. Typically, prior to initiation of thetreatment process, the region to be treated will be immobilized by oneof any number of such devices currently used in radiation therapy orthat are developed specifically for the region in question. However,even following such immobilization, it is possible for the patient tomove or to move the portion of their anatomy in which the treatmentregion lies. If such should occur while the treatment is underway, anincorrect dose might be delivered to the region being treated as well asto regions that are not to be treated.

The disclosed device can include any number of means for monitoringpatient movement during the course of treatment in order to ensure thatthe treatment is not delivered to an incorrect location as shown in FIG.21. One embodiment comprises an x-ray sensitive plate such as anamorphous silicon panel 210 or other means for recording the passage ofradiation positioned under the region to be treated 211 that ismonitored in real time by a control system. On the underside or back ofthe region to be treated are placed several small radiopaque markers 212or an array of markers or patterned marker system such as a divergingtriangle with radiopaque legs or a simple grid of radiopaque lines 213.At the time that the surface is “traced” or scanned by the robot system214, a small amount of low energy radiation 215 can be used to take acontinuous set of “images” of the markers, each of which correlates tothe recorded position of the robot relative to the markers at the timethe image are taken. At the time of treatment, an additional series ofcontinuous images can be taken of the markers for each indexed positionof the robot arm. The control system can correlate the position of themarkers on the treatment images to the position of the markers on thelocalizing images for a given position of the robot. If the positionsare the same the treatment is allowed to continue. If the positions aredifferent, then that implies that the treatment region has moved.

The robot can be used in another fashion to determine movement prior tothe start of treatment but not during treatment. At the time of regionidentification (time1) and prior to start of treatment (time2), the usercan manually identify marks on the region surface or markers placed onthe region surface. If the position of these marks or markers haschanged between time1 and time2, then movement has occurred.

Other methods for accomplishing the same include the use of alocalization system to track markers placed on the tissue surface in thevicinity of the region being treated. The location of the markersdetermined at the time of region identification is used as a baseline.At the start of and during treatment the position of the markers aredetermined continuously or intermittently and compared to the baselineposition in order to determine if movement, and how much movement, hasoccurred. For instance, cameras 226 can be used that monitor passive oractive markers 227 secured to the patient surface near the region beingtreated. A magnetic localization system also could be used in place ofthe camera system as could any other means for acquiring the 3-Dposition of markers affixed to the region being treated such as but notlimited to an infrared localization system, a sound-based localizationsystem, and a laser range finder system. Another means of accomplishingthe same involves using a laser scanning device to scan the region inquestion. Following an initial scan that acts as a baseline, subsequentscans generated during the course of treatment can be compared to thebaseline image in order to determine if movement has occurred.

As an additional means of determining if movement has occurred betweenthe time of region identification and the start of treatment, it ispossible to use the robot to retrace the region, or to identify specificportions of the region, or marks places on the patient at the time ofregion identification that are identified initially at the time ofregion identification, before treatment begins. The new data is comparedto the data acquired at the time of region identification in order todetermine if movement has occurred between the time of regionidentification and the start of treatment.

An indication by any of these means that the patient has moved can causethe control system to shut down the treatment. Alternatively, the systemcan continue the treatment while compensating for movement bydetermining the vector and amount of movement and changing the deliveryinstructions for the delivery device such as a robot so that itpositions the delivery arm correctly for the new position of thepatient. In most cases the movement will be small and can be correctedin this manner. If the movement is outside the ability of the system tocorrect, such as if the patient gets up off the treatment table or ifthe patient lifts an arm undergoing treatment off of the table, thetreatment can be terminated until corrections are made.

Targets Distance from Delivery Device

Although the methods and apparatus described so far will increasesignificantly the dose at depth compared to the dose at the tissuesurface, this increase may not be great enough to treat targets locateddeep to the tissue surface that are not targeted directly by a needlebut treated instead by an external approach. At a typical deep targetdepth of 10-30 cm, the residual dose to a 4 cm target volume from anunmodified low energy x-ray source will be on the order of 0.001-0.1% ofthe dose at the tissue surface (assuming a half-value layer in tissuefor a 50-70 kvp beam of 2 cm). Using the techniques described above, theresidual dose to a 4 cm target at a target depth of 10-30 cm can beincreased to as much as several percent. This obviously is not enough toallow the treatment of such deep lesions.

2-D Array

It is possible however to furthermore enhance the methods and apparatusherein described such that it can be used to treat such deep lesions.The first step in so doing is to increase the actual dose delivered bythe apparatus itself while reducing surrounding dose. This inventionincludes several means for achieving said increase, as applied to thepreferred embodiment using the scanning electron apparatus describedpreviously and illustrated in FIG. 16A-B, although other of the meansdescribed herein can be used as well, specifically the embodimentemploying a single or plurality of small x-ray sources used to create a2-D array of beam emitters. However, it is required that an effectivetwo-dimensional array of beams be used to treat the patient; this willincrease significantly the number of beams that hits the target therebyincreasing dose.

Convergent Beam Delivery

A second means changes the delivery geometry of the treatment. Element246 in FIG. 24A illustrates the parallel geometry applied to acollimator that would be part of an electron-delivery device 245 asdescribed previously in FIG. 10A-10C; FIG. 24B element 248 shows thebeam that would result from such a collimator. In the followingadditional embodiment, the geometry is changed to one that isconvergent, using a collimator 247 in FIG. 24A generating beam 249 asdepicted in FIG. 24B. The major benefit of a convergent set of beamsrather than a parallel set of beams is that more of the dose isrestricted to the desired region of tissue. This results in the dose tonontarget tissue being lower than would be possible with a parallel beamarrangement. In order for all beams to converge on a target at depth,each hole in the collimator plate must be formed to generate differentshaped and directed beams of radiation, such as beams 251-253 in FIG.25A. However, each beam of radiation still passes through a uniquesection of tissue surface. In addition, there must be a different set ofradiation transmissive passages for targets of different sizes, such asa small target 254 in FIG. 25B and a larger target 255 in FIG. 25C. Notethat the collimator plates 256 for the small target and 257 for thelarge target have a different orientation and shape to each transmissivepassage through the collimator plate.

Assuming that target volumes are always treated at a given depthrelative to the beam generation device itself, an approach that isstandard practice in radiation therapy, it is possible to manufacture aseries of collimator plates with each one used to create a specific sizetarget at a given depth. However, since the size of targets that need tobe treated can vary over a large range, from under 1 cm to as large as10 cm or more, this will require a very large number of plates or a verycoarse resolution in terms of the sizes of volumes that have acollimator appropriate to their size. Therefore herein is disclosed ameans for using a single collimator system with transmissive passagesall formed in the shape and orientation such that a convergent beamgeometry will result for a range of target volumes. FIG. 26A describes aone-dimensional version of a two dimensional collimator plate geometrywith each transmissive passage of a different shape and orientation suchthat all beams will converge at a specific depth SAD. FIG. 26B describesa similar collimator plate but with each passage of the same shape andorientation. By taking the collimator plate in FIG. 26B and bending itso that it follows the surface of a sphere of a radius equal to the samedepth SAD, all beams will be made to converge as in FIG. 26C but will begenerated by a collimator plate where the transmissive passages aremanufactured so that they are initially parallel. Beam size adjustmentwith infinite resolution can now be achieved by applying this concept tothe collimation system described in FIG. 23, as now depicted in FIG. 27.Four identical plates 274-277 are arranged in pairs, 275/277 and274/276, that are orthogonal to each other; to adjust the size of all ofthe transmissive passages simultaneously each plate is slid along itsdescriptive arc instead of along a flat plane as in FIG. 23.

As presented previously, the dose at a depth of 10 cm from a single beamof heavily filtered low energy radiation, say 50-120 kvp, will beapproximately 3-20% of the dose at the skin surface; at 30 cm this willbe reduced to 0.001-0.4%.

TABLE 1 Approximate DD for Various HVL % DOSE for HVL DEPTH (cm) 2 2.5 34 0 100.0 100.0 100.0 100.0 5 10.0 12.5 20.0 40.0 10 3.0 6.3 10.0 22.015 0.5 1.6 3.0 7.0 22 0.1 0.2 0.7 2.0 30 0.0 0.0 0.1 0.5

This is shown in FIG. 28. In FIG. 28A, the normal depth dose curves fora range of beam energies are shown; each curve is the depth dose for anenergy with a half value layers (HVL) ranging from 2 to 4 (equivalent toa range of energy of from approximately 50-120 k; the greater the beamenergy the greater the half value layer), given as percent dose versusrelative depth (in this case depth ranges from 0 to 30 CM depth intissue).

Energy Modulation

A typical scanning electron beam delivery system as described hereinwill generate 10,000 or more effective beams of radiation evenly spacedthat will converge on the target volume thereby increasing the dose atdepth significantly. However, the increase in dose at depth is not afactor of 10,000 because some of these beams will begin to overlapoutside the target volume, the number increasing as the depth of thetarget decreases (assuming a fixed focal length for beam convergence).Beams will overlap to a greater and greater degree as they transversetissue on their way to the target. At the same time, the depth dose foreach beam will decrease due to tissue attenuation. Thus the actualincrease in effective dose will depend on the delivery geometry, thesize of the target, and the beam energy. The depth dose curves for thesame HVL but using the herein described methods and apparatus forconverging the beams at depth are shown in FIG. 28B as applied to a 4 cmtarget and FIG. 28C as applied to a 10 cm target. The focal distance forbeam convergence is kept at a constant 30 cm for all deliveries. Therelated values in tabular form are presented in Table 2 for a 4 cmtarget 30 cm deep and in Table 3 for a 10 cm target.

These are believed to be representative values for the techniquedescribed and are not actual or measured values. Note that in both ofthese cases the maximum dose moves deeper in tissue as the half-valuelayer or energy increases. Thus it is possible to vary the depth atwhich the maximum dose will be delivered merely by changing beam energywhile leaving focal depth and depth in tissue the same. That is, in FIG.29 if using an array 296 of beams to treat the target volume 295 locatedat 10 cm in patient 297, rather than changing the delivery geometry froma focal point 30 cm deep in tissue as in FIG. 29A to one that is 10 cmdeep in tissue as in FIG. 29B, the geometry can be left untouched withonly the energy being changed—this will move the point of maximum doseto a more shallow point in tissue as in Table 3.

TABLE 2 Approximate DD for HVLs Using Disclosure 4 cm Target % DOSE forHVL DEPTH (cm) 2 2.5 3 4  0  38%  21%  11%   3%  5 100%  99%  55%  30%10  85% 100%  86%  56% 15  44%  80%  81%  56% 22  24%  53% 100%  85% 30  7%  25%  68% 100%

TABLE 3 Approximate DD for HVLs Using Disclosure 10 cm Target % DOSE forHVL DEPTH (cm) 2 2.5 3 4  0  38%  24%  16%   7%  5 100% 100%  55%  30%10  72%  94% 100%  68% 15  34%  69%  86%  92% 22  13%  33%  77% 100% 30  1%   4%  15%  34%Multiple Field Treatment

Even with this approach, the dose at depth is only increased to atherapeutic ratio of about 1:1. A second means and apparatus willimprove even further the dose at depth relative to anywhere else whilereducing even further dose to surrounding tissue as well as the surfacedose. The scanning electron radiation device, or other embodiments asdescribed previously herein, can be secured to a c-arm or similar device301 in FIG. 30A-B that is used to position the array at a plurality ofpositions, defined as multiple fields (MF) as in FIG. 30B distributedaround the patient 303 in FIG. 30C with the delivered fields ofradiation converging on the target volume 302. As is the case with mostrotational techniques, this will concentrate a greater number of beamson the target tissue and not on nontarget tissue. By picking a number offields appropriate to the size and location of the target, dose at depthcan be increased significantly. For instance, by using six fields evenlyspaced for a 10 cm target the related values would be as in Table 4 andFIG. 31.

TABLE 4 Approximate DD for HVLs Using Disclosure 10 cm Target MultipleFields % DOSE for HVL DEPTH (cm) 2 2.5 3 4  0   6%   4%   3%   1%  5100%  18%  11%   6% 10  12% 100%  19%  11% 15   6%  12% 100%  15% 22  2%   6%  15% 100% 30   0%   1%   3%   6%Dose Enhancement

This improvement in therapeutic ratio, roughly equal to the number offields used, although quite significant, may be enough for afractionated treatment but may be not enough to deliver the doserequired for killing all malignant cells, believed to be in excess of25-50 Gy in a single fraction, without damaging normal tissue (believedto be 5 Gy maximum tolerated dose in a single fraction but ideally lessthan 2 Gy). This is especially the case if a number of large doses areto be used in order to deal with the problem of radioresistant cells inthe center of a target volume. In this case, it would be ideal todeliver a large tumorcidal dose in one fraction to the radiosensitivecells that are oxygenated, then after they die and the inner cells areoxygenated, deliver another large tumorcidal dose, repeating thisprocess as many times as is required in order to kill all cells oncethey are oxygenated.

However, the ability to get a sizeable dose at depth from low energyx-rays in the range of 50-120 or more kvp makes it possible to benefitfrom the practice of dose enhancement in order to improve even furtherthe therapeutic ratio. Dose enhancement (DE) occurs if radiation isdelivered to an interface between normal tissue and a high z material. Aphoton, of an energy near the absorption energy of an inner electronshell in the target material, transfers its entire energy to theelectron that subsequently is ejected from the atom (photoelectron). Therelatively low kinetic energy of the ejected photoelectron is equal tothe incident X-ray photon energy minus the binding energy of theelectron. The vacancy in the electron orbital resulting from theelectron ejection is filled by an electron from an outer orbit (with alower binding energy), leaving a vacancy in this outer orbit that inturn is filled by another electron from an orbit even further away fromthe nucleus. The surplus energy liberated when an electron drops from anouter shell to a shell closer to the nucleus results either in theemission of a fluorescent photon or in the ejection of an additionalsecondary electron (Auger electron) from the same shell. If Augerelectron emission occurs, the atom is left in a doubly ionized state(due to two ejected electrons) that is resolved by the dropping of otherelectrons from outer shells to fill the holes. This cascade processresults in the release of a large number of very low energy electronsthat travel very short distances and deposit their energy (track ends)locally (therefore with a very high linear energy transfer (LET)). Ifthe electrons are produced near the DNA they can be very effective inkilling the cell through double strand breaks.

The depth of penetration of Auger electrons is very small, on the orderof 1-10 micrometers. Thus reliable cell death requires that the Augerelectron be generated within 1-10 micrometers of the DNA, e.g. withinthe cell (and preferably within the nucleus) itself. The disadvantage ofthis approach is that the process for generating the Auger electronsmust take place within the cell. The advantage is that the tumorcidaleffect of the radiation is limited to the target cells. As a result,such a therapy has the potential for repetitive dosing with minimaltoxicity.

Gold Nanoparticles

In the preferred embodiment gold nanoparticles are used in associationwith the scanning electron system delivering convergent beams ofradiation of variable energy that have been filtered and collimated,although other high z materials, other size particles, and other meansof delivering convergent beams of radiation can be used as well. Thesegold particles can be of any size (FIG. 32B) or shape (FIG. 32A) and canbe solid, hollow, or consist of a gold shell surrounding a core of someother material such as silica or iron or some other material (FIG. 32C)or any other construct ranging in size from several nanometers to evenmicrons or millimeters in size. The gold surface of the nanoparticles,be they solid or hollow, provides a simple chemistry for theself-assembly of polyethylene glycol, antibodies, dendrimers, aminoacids, or other agents that allow the nanoparticles to accumulate in thevicinity of, or to attach directly to or in, or be preferentially takenup by, the targeted cells and not in the vicinity of, or attacheddirectly to, or taken up preferentially by, or in normal cells. Thenanoparticles and their carriers or attachments can be delivered by IVinjection, injected directly into the region of the tumor, or sprayeddirectly onto the target (if accessible), and can accumulate inconcentrations sufficient to blanket all cells in the target volume tosome degree.

Dose enhancement secondary to the release of Auger electrons from goldparticles or other metals will occur when using most energies in thekilovoltage or orthovoltage range. Experimental studies using gold foilhave shown that gold particles, when exposed to heavily filtered 50-70kvp x-rays, generate a dose enhancement factor believed to be in excessof 150; the use of heavily filtered 100-120 kvp x-rays results in a doseenhancement factor believed to be greater than 50; the amount of doseenhancement is dependent on the match between the energy of theradiation and the energy of K, L, and M electron shells of the particlebeing used. In practice, however, the amount of enhancement that will beachieved in normal clinical conditions is much less as a result of thelimited concentration of particles that can be achieved in targettissues relative to a piece of gold foil and the reliability ofdelivering the particles to the target tissue. The actual doseenhancement factor is related to the fraction of mass of the gold intissue. Realistic numbers for dose enhancement based on experimentalstudies are believed to be in the range of 2-10× for the lower energyrange and 1.3 to 3× for the higher energy range depending on beam energyand tissue concentration.

Even this degree of enhancement may not be enough to generate a usefultreatment paradigm at the depth at which many tumors occur when usingunmodified or even heavily filtered low energy radiation. Assume thevalues presented previously for unmodified kvp depth doses—3-20% of thedose at 10 cm and at 30 cm 0.001-0.4%. Multiply these by the number offields to be used—6—and the dose enhancement factor—ranging from 10 forthe lowest energies to 3 for the highest. This results in a best dose of200% at 10 cm depth and 10% at a 30 cm depth. Even if the doseenhancement were increased by a factor of two at high energies and twicethe number of fields were used, the resultant dose at a 30 cm depthwould still be less than 25%.

Convergent 2-D Array Delivery, Multiple Fields, and Dose Enhancement

However, when the degree of dose enhancement achieved through the use ofgold particles is coupled with the amount of dose that can be deliveredto depth using the methods and means disclosed herein, a therapeuticdose can be achieved. Assume the values in Table 2 and Table 3 for 4 cmand 10 cm targets located at varying depth and use a combined “doseenhancement times multiple fields” factor of 12-60 for the lower energyranges (3 to 10 DE times 6 fields) and 8-18 for the higher energies (1.3to 3 DE times 6 fields). It thus becomes possible to deliver a dose to atarget volume at a depth that will be greater by a factor of 20 or morecompared to the dose delivered to the rest of tissue outside thetreatment volume as shown in Table 5 and in FIG. 33. If higher energiesare used a dose of a similar relative magnitude can be delivered totargets that are even 10 cm or greater in size at depths of 30 cm orgreater; the dose enhancement effect is less but the dose delivered atdepth by the techniques described herein is higher, thereby producing agreater effective dose at deeper depth.

TABLE 5 Approximate DD for HVLs Using Disclosure 10 cm Target MF & DE %DOSE for HVL DEPTH (cm) 2 2.5 3 4  0   1%  1%  1%  0%  5 100%  3%  3% 2% 10   1% 100%  5%  4% 15   1%  2% 100%  5% 22   0%   1%  4% 100% 30  0%   0%  1%  2%Range Modulation

It is also possible to concentrate dose by keeping the focal distancethe same while bringing the focal spot to overlap on the target volumeby moving the delivery device farther away from the patient surface.This will increase the dose delivered to the target because of themaximum concentration of beams but will also increase the number ofbeams that cross at shallower depths, as shown in Table 6 for a 10 cmtarget, and therefore increase the dose at shallower depths (assumes a30 cm focal spot, 10,000 beams total distributed equally from a deliveryplate of 40 cm×40 cm converging on a 10 cm diameter target).

However, the net result is the ability to position the location ofmaximum dose at the focal point, i.e. the target location, as can beseen in Table 7 as well as in FIG. 34. Thus it is possible to deliverserial radiosurgical or large single fraction doses (25-50 Gy) to killmalignant cells as they become oxygenated due to the death ofsurrounding cells since the dose to normal cells would be less than 2.5Gy with one or both of the approaches.

Of course, different metals or high Z materials can be used in place ofgold in the same manner as described above. The actual gain intherapeutic ratio would be determined by the maximum amount of doseenhancement, the amount of material in the tissues, and the % depth dosefor a given metal and energy. However, the magnitude of the effectsdescribed herein will not be seen with energies in the MV range.

TABLE 6 Number of Beam Crossings with Varying Focal Spot Depth NUMBER OFBEAMS CROSSING DEPTH (cm) 30 cm 25 cm 20 cm 15 cm 10 cm 5 cm 0 11 200400 2,000 5,000 10,000 5 200 400 2,000 5,000 10,000 10,000 10 400 2,0005,000 10,000 10,000 10,000 15 2,000 5,000 10,000 10,000 10,000 5,000 205,000 10,000 10,000 10,000 5,000 2,000 25 10,000 10,000 10,000 5,0002,000 400 30 10,000 10,000 5,000 2,000 400 200 35 10,000 5,000 2,000 400200 11 40 5,000 2,000 400 200 11 0 45 2,000 400 200 11 0 0 50 400 200 110 0 0

TABLE 7 Approximate DD for 4 cm HVL with Varying Focal Spot Depth % DOSEfor Different Focal Depths DEPTH (cm) 30 cm 25 cm 20 cm 15 cm 10 cm 5 cm0  1%  9%  7%  16%  19%  14% 5  9%  7%  14%  16%  15% 100% 10  7%  14% 13%  12% 100%  2% 15  16%  16%  12% 100%  3%  0% 20  17%  14% 100%  2% 1%  0% 25  13% 100%  2%  0%  0%  0% 30 100%  2%  0%  0%  0%  0%Targeting

Because the toxic effect of the treatment occurs only where the regionsof metal or high Z nanoparticles and low dose radiation overlap, thisapproach is relatively insensitive to target volume movement duringtreatment. That is, as long as the radiated volume is large enough sothat the cancer cells always lay within the radiated field, the cellswill receive a lethal dose of radiation. Since the toxicity of theradiation alone can be kept relatively low (the lethal dose resultingfrom the combination of the delivered radiation times the enhancementfactor), it does not matter if a somewhat increased volume of normaltissue is exposed to the radiation beam. This is in distinct contrast totypical radiation therapy, where much time and money and equipment isdevoted to limiting the amount of normal tissue that is exposed to anyradiation at all because the dose is high enough to cause toxicity.

This factor is important when considering treating cancers that aredisseminated or have metastasized. In these cases, the nanoparticleslabeled with antibodies or markers specific to the cancer cells willbind to the cells wherever they exist, even if that is outside theprimary region of tumor. Since the approach disclosed herein isessentially nontoxic to non-cancerous cells, the radiation field can beenlarged to encompass cancer cells wherever they might be as determinedby diagnostic imaging or by clinical judgment. This would not bepossible when using conventional radiation where there is inverserelationship between the amount of dose one can deliver and the size ofthe region to which that dose is delivered.

In addition, since only cancer cells would be labeled, or would belabeled preferentially, with nanoparticles by the means describedherein, and only cells that are so labeled will experience doseenhancement, non-cancerous cells lying within a tumor or target volumewill be spared the most toxic effects of the radiation and may survivetreatment.

Calibration and Monitoring of Therapy with Treatment Beams

As mentioned previously, one of the factors determining the amount ofdose enhancement is the concentration of Z material in the target. Thiscan be assessed by using the array of beams used to deliver thetreatment dose to also image the target volume. An x-ray detector 352can be positioned 180 degrees opposite the beam array 351 in order tocapture the radiation 354 as it diverges after exiting the patient 353in FIG. 35A. Alternatively the radiation could actually be focused onthe detector 355 in FIG. 35 B with an appropriate choice of energy usedto deposit maximum dose at the target region 355 in patient 353 as inFIG. 35B-FIG. 35C. The imaging characteristics of the target region astraversed by the array of beams can be determined prior to and followingloading of the target with the Z material. Once a calibration curve iscreated relating concentration to change in imaging characteristics,this curve can be used to determine the concentration of Z material inthe target volume. This concentration can then be used by a planningsystem to determine the appropriate values to be used for planningvariables such that the desired dose can be delivered to the targetregion. The same detector can be used to localize the patient and todetermine if the patient has moved by comparing imaging characteristicsprior to and during treatment using the methods and means presentedpreviously.

This combined approach may allow most tumors to be treated in a singlefraction or very few fractions without risking damage to normal tissue.As mentioned it will also allow a serial radiosurgical treatment to beimplemented whereby large single fraction doses are delivered repeatedlyover time in order to kill cancer cells as they become oxygenated andtherefore active. It will also do so in a very cost-effective manner.Unlike complex IMRT and IGRT capable megavoltage delivery devices thatrange in price from $3 M to in excess of $4 M depending on features,that require specially constructed rooms that may cost in excess of anadditional $1 M to build, and that are quite time consuming when itcomes to the planning and delivery of the treatment dose, low energydevices are low cost, easy to build, and can be made very compact.Unlike other low energy radiation devices that have been proposed foruse, this invention will deliver the dose of radiation required tobenefit from dose enhancement at a reasonable cost and in a reasonableamount of time regardless of the size or depth of the target region. Theuse of low energy reduces the need for user and patient shielding,making the device installable in almost any environment, increasingsafety and reducing significantly the cost of building a treatmentfacility.

Other Variations

Each of the planning, localization, guidance, and monitoring featuresdescribed herein can be applied to the convergent approach utilizingdose enhancement. In addition, many variations of the invention willoccur to those skilled in the art. All such variations are intended tobe within the scope and spirit of the invention. For instance:

-   (a) Multiple delivery units could be affixed to a C-arm device in    order to improve efficiency of treatment delivery, or one head can    be used for imaging, with a focal point outside the patient, and    another for treatment with a focal point inside the patient.-   (b) A variation for delivering the 2-D array of beams required for    the convergent therapy would be to use a rotational support    structure generating a 1-D array of beams that not only can rotate    around a patient but also can angle its plane of rotation along an    arc perpendicular to the initial plane of rotation. In this manner    the rotational support would be indexed orthogonal to the plane of    rotation between repeated rotations, thereby reproducing the 2-D    array. That is, after the rotational tool has positioned the 1-D    array in a plurality of positions around the patient along a single    rotation around the patient, the rotational device is rotated    perpendicular to the prior plan of rotation by an amount sufficient    to reposition the array in the correct increment, thereby creating a    new arc about which to rotate the device. By repeating this process    many times, it is possible to create an effective 2-D array of beams    delivered to the patient from a plurality of positions about the    patient.-   (c) The anode plate used in the scanning electron beam system can    contain any number of targets all of which are not required to be    activated in the course of a scan. For instance, assuming a 50 cm×50    cm plate containing 200×200 targets, in some applications all    targets will be scanned whereas in some cases alternating rows will    be scanned such that only 100×100 targets are used creating an    effective 2× spacing between the beams. Alternatively, an area of    the plate only 10 cm×10 cm will be used. In each instance a    different beam overlap geometry will be created resulting in a    different and unique set of depth dose curves that can be tailored    for the clinical condition to be treated.

Although some embodiments are shown to include certain features, theapplicant(s) specifically contemplate that any feature disclosed hereinmay be used together or in combination with any other feature on anyembodiment of the invention. It is also contemplated that any featuremay be specifically excluded from any embodiment of an invention.

What is claimed is:
 1. An apparatus for performing radiation therapy ona selected region of a tissue in proximity to said apparatus, saidapparatus comprising: a radiation source for generating beams of lowenergy radiation; a positioner for disposing said beams in a precise andcontrollable manner from a plurality of positions indexed relative toeach other in predetermined but variable millimeter or submillimeterincrements so as to produce an at least one-dimensional array of saidbeams that overlap in increasing amounts as said beams pass through saidtissue, whereby an amount of radiation delivered at depth in said tissueis equal to or greater than a dose delivered to the tissue through whichthe beams pass; an attenuator for attenuating each beam of radiation bya variable and predetermined and known amount so as to harden each saidbeam; and a treatment planner for creating a treatment plan wherein saidtreatment plan comprises at least said amount of radiation delivered tosaid depth and a location of said depth, wherein said treatment plannerat least in part is configured to communicate said treatment plan tosaid radiation source and to said positioner.
 2. The apparatus of claim1 further comprising: an imaging device for imaging markers placed on anunderside of a patient; a detector for detecting the radiation producedby the radiation source as the radiation exits the patient and passesthrough the markers whereby a difference in a position of said markersbetween a time of region identification and a start and process ofdelivering a treatment can be determined, and whereby said treatment canbe adjusted automatically to compensate for detected movement in orderto insure that the treatment is not delivered to an incorrect location.3. An apparatus for delivering a dose of radiation to a region of tissuein a patient, said apparatus comprising: a radiation source forgenerating beams of low energy radiation; a positioner for disposingsaid beams in a precise and controllable manner from a plurality ofpositions indexed relative to each other in predetermined but variablemillimeter or submillimeter increments so as to produce atwo-dimensional array of beams that overlap and converge at apredetermined but variable depth in tissue, whereby amount of radiationdelivered to the region is increased relative to a dose delivered to thetissue through which the beams pass; and an imaging device for imagingsaid beams after said beams pass through the patient comprising an x-raydetector interposed in a beam path outside the patient whereby at leastone of a target location, amount of Z material in the region, andeffects of treatment can be determined.
 4. The apparatus of claim 3wherein the radiation source further comprises a scanning electron beamdevice.
 5. A method for delivering a dose of radiation to a region oftissue in a patient comprising: positioning a beam of radiation togenerate a plurality of beams of low energy radiation indexed relativeto each other in predetermined but variable increments; creating atwo-dimensional array of overlapping beams that converge at a specifiedbut variable depth; increasing a dose of radiation delivered at depth tothe region relative to a dose delivered to other tissue; imaging saidregion using said array in conjunction with a detector placed in a pathof said array as said beams exit the patient; delivering said array froma plurality of directions; adjusting a depth of maximum dose from saidarray by varying an energy of said array or a focal point of said array;collimating in a variable but predetermined way said beams in order tocontrol an amount of spread of the beam with increasing depth;transferring data from said detector into a treatment planning system;entering into said planning system the dose of radiation to be deliveredto said region and a thickness of said region and a position of saidregion relative to a tissue surface; and generating a treatment plan forsaid region specifying at least the plurality of positions, acollimation for said array, the energy for said array, and a dose to bedelivered at each of said positions, whereby an entire process oftreatment, from region identification to treatment planning to treatmentdelivery can occur in a single setting in a fully integrated manner.